PK and Safety of Paclitaxel Injection Concentrate for Nano-dispersion Alone and in Carboplatin Combination

• Determination of MTD [ Time Frame: One 21-day treatment cycle ] [ Designated as safety issue: Yes ]
  MTD for PICN in combination with carboplatin will be determined. MTD will be defined as the PICN dose below the dose at which DLT (Dose Limiting Toxicity) is seen for ≥ 2 subjects.
  
  

• Establishing the pharmacokinetic profile [ Time Frame: One 21-day treatment cycle ] [ Designated as safety issue: No ]
  Plasma levels of PICN and Carboplatin will be determined and PK parameters viz. Cmax, AUC0-t, AUC 0-∞, MRT, Tmax, t½ , Kel, Vd for PICN in combination with carboplatin will be evaluated.
  
  

Drug: Paclitaxel Injection Concentrate for Nanodispersion

The PICN infusion will be prepared by diluting in 5 % Dextrose Injection to obtain a nano-dispersion and infused using conventional PVC infusion systems.

In Part A, PICN will be administered and in Part B, PICN and Carboplatin will be administered every 3-weekly until disease progression, development of unacceptable toxicities, non-compliance, intercurrent illness that prevents treatment continuation, withdrawal of consent, or change in subject condition that render the subject unacceptable for further treatment.

This is a phase I study of PICN alone and in combination with carboplatin in subjects with advanced solid malignancies. It will be conducted as a two-part study (Part A followed by Part B).

Part A will characterize the pharmacokinetic profile of PICN at 3 dose levels administered as 30-min infusion to separate groups of 3 subjects.

Part B will start upon completion of Part A and will use the standard '3+3' dose-escalation design to determine the Maximum Tolerated Dose (MTD) and recommend phase II dose of PICN in combination with carboplatin. Both PICN and carboplatin will be administered on day 1 and will repeat every 3 weeks (1 cycle). Carboplatin dose is fixed at AUC 6 and PICN will be administered at escalating doses till Dose Limiting Toxicity (DLT) is observed. The dose escalation plan is as follows: 3 subjects will be treated at the initial dose level for PICN with carboplatin at AUC 6. If no cycle-1 dose-limiting toxicities (DLTs) are observed, 3 additional subjects will be treated at the next dose level. If one of 3 subjects experiences a DLT at any given dose level, 3 additional subjects will be treated at that same dose. If a DLT occurred in at least 2 subjects at any dose level, dose escalation will be halted, and the next 3 subjects enrolled will be treated at the preceding lower dose level. MTD will be defined as the dose below which DLT is seen for ≥ 2 subjects in cycle 1. At least 6 subjects will be treated at the MTD. Subjects who fail to complete 1 cycle of study treatment for non-treatment related reasons will be replaced.

AEs will be monitored across all cycles per CTCAE. Subjects will continue therapy until disease progression, development of unacceptable toxicities, non-compliance, intercurrent illness that prevents treatment continuation, withdrawal of consent, or change in subject condition that render the subject unacceptable for further treatment. Upon study completion, subjects will be followed for toxicities for 4 weeks, or longer if there are unresolved ≥ grade 3 toxicities at the end of the 4-week period. Subjects removed from study for unacceptable adverse events will be followed until resolution (≤ grade 2) or stabilization of the adverse events. Blood samples for PK studies will be collected at pre-planned time-points.